rs150384171

Variant names:

• chr19-8305034-ACTC-A
• rs150384171
• NM_016579.4:c.262_264delGAG

Your query was ambiguous. Multiple possible variants found:

• chr19-8305034-ACTC-A
• chr19-8305034-ACTC-ACTCCTC

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PM4_Supporting BS2

The NM_016579.4(CD320):​c.262_264delGAG​(p.Glu88del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0107 in 1,606,154 control chromosomes in the GnomAD database, including 102 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars).

• Frequency:
  • Genomes: 𝑓 0.0080 (7 hom., cov: 33)
  • Exomes 𝑓: 0.011 (95 hom.)
• Consequence: CD320 NM_016579.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:3 U:2 B:4 O:1
• Conservation: PhyloP100: 0.450
• Publications: 16 publications found

Genes affected

CD320 (HGNC:16692): (CD320 molecule) This gene encodes the transcobalamin receptor that is expressed at the cell surface. It mediates the cellular uptake of transcobalamin bound cobalamin (vitamin B12), and is involved in B-cell proliferation and immunoglobulin secretion. Mutations in this gene are associated with methylmalonic aciduria. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Jan 2011]

CD320 Gene-Disease associations (from GenCC):

• methylmalonic acidemia due to transcobalamin receptor defect

  Inheritance: Unknown, AR Classification: DEFINITIVE, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet, ClinGen, Laboratory for Molecular Medicine

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_016579.4. Strenght limited to Supporting due to length of the change: 1aa.
• BS2: High Homozygotes in GnomAd4 at 7 Unknown,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CD320	NM_016579.4	c.262_264delGAG	p.Glu88del	conservative_inframe_deletion	Exon 2 of 5	ENST00000301458.10	NP_057663.1
CD320	NM_001165895.2	c.143-949_143-947delGAG		intron_variant	Intron 1 of 3		NP_001159367.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CD320	ENST00000301458.10	c.262_264delGAG	p.Glu88del	conservative_inframe_deletion	Exon 2 of 5	1	NM_016579.4	ENSP00000301458.4

Frequencies

GnomAD3 genomes AF: 0.00803 AC: 1216 AN: 151518 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00293

Gnomad AMI AF: 0.0165

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.0124

Gnomad SAS AF: 0.00271

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0105

Gnomad OTH AF: 0.00673

GnomAD2 exomes AF: 0.00936 AC: 2299 AN: 245504 AF XY: 0.00905

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.0142

Gnomad ASJ exome AF: 0.0104

Gnomad EAS exome AF: 0.0124

Gnomad FIN exome AF: 0.00437

Gnomad NFE exome AF: 0.0107

Gnomad OTH exome AF: 0.00837

GnomAD4 exome AF: 0.0110 AC: 15935 AN: 1454522 Hom.: 95 AF XY: 0.0107 AC XY: 7730 AN XY: 723916

African (AFR) AF: 0.00224 AC: 75 AN: 33452

American (AMR) AF: 0.0140 AC: 625 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00965 AC: 252 AN: 26116

East Asian (EAS) AF: 0.0102 AC: 405 AN: 39674

South Asian (SAS) AF: 0.00322 AC: 278 AN: 86216

European-Finnish (FIN) AF: 0.00372 AC: 175 AN: 47026

Middle Eastern (MID) AF: 0.00111 AC: 6 AN: 5384

European-Non Finnish (NFE) AF: 0.0121 AC: 13470 AN: 1111696

Other (OTH) AF: 0.0108 AC: 649 AN: 60258

GnomAD4 genome AF: 0.00802 AC: 1216 AN: 151632 Hom.: 7 Cov.: 33 AF XY: 0.00791 AC XY: 586 AN XY: 74058

African (AFR) AF: 0.00292 AC: 121 AN: 41368

American (AMR) AF: 0.0137 AC: 208 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.0125 AC: 64 AN: 5136

South Asian (SAS) AF: 0.00271 AC: 13 AN: 4794

European-Finnish (FIN) AF: 0.00315 AC: 33 AN: 10486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0105 AC: 713 AN: 67848

Other (OTH) AF: 0.00666 AC: 14 AN: 2102

Alfa AF: 0.00232 Hom.: 1

Bravo AF: 0.00830

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0116

EpiControl AF: 0.0101

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:3 Uncertain:2 Benign:4 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3 Other:1

Feb 02, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2017

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CD320: PM4:Supporting, BS1, BS2 -

Aug 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM4 -

May 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 20524213, 29040465, 29663633, 30041674, 22819238, 31180159, 31462756) -

Methylmalonic acidemia due to transcobalamin receptor defect Pathogenic:2 Uncertain:1 Benign:1

Aug 01, 2010

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

Aug 22, 2023

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 28, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant, c.262_264del, results in the deletion of 1 amino acid(s) of the CD320 protein (p.Glu88del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs150384171, gnomAD 1.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with methylmalonic aciduria (PMID: 20524213, 22819238, 29663633, 34978764; internal data). ClinVar contains an entry for this variant (Variation ID: 203643). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on CD320 function (PMID: 20524213, 27411955). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

CD320-related disorder Pathogenic:1

Jun 12, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CD320 c.262_264delGAG variant is predicted to result in an in-frame deletion (p.Glu88del). This variant has been reported in the homozygous or compound heterozygous state in patients with methylmalonic acidemia and homocysteinemia due to transcobalamin receptor deficiency (e.g., Quadros et al. 2010. PubMed ID: 20524213; Karth et al. 2012. PubMed ID: 22819238; Hannah-Shmouni et al. 2018. PubMed ID: 29663633; Pappas et al. 2022. PubMed ID: 34978764). Fibroblast cells from patients apparently homozygous for the CD320 c.262_264del (p.Glu88del) variant showed reduced uptake of holo-transcobalamin (holo-TC) as well as elevated levels of homocysteine and methylmalonic acid in culture medium (Quadros et al. 2010. PubMed ID: 20524213; Pangilinan et al. 2022. PubMed ID: 35107211). The c.262_264del variant has been reported in a large population database at an allele frequency of up to ~1.4%, which would be high for an autosomal recessive disorder with a severe phenotype. It should be noted, however, that most reported patients with transcobalamin receptor deficiency have been clinically asymptomatic. These data suggest that this may possibly be a benign biochemical phenotype, although the long-term outcome in these individuals is not currently well understood (Hannah-Shmouni et al. 2018. PubMed ID: 29663633). In summary, we classify the c.262_264del (p.Glu88del) variant as likely pathogenic for recessive transcobalamin receptor deficiency. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.45
Mutation Taster		=63/37	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs150384171; hg19: chr19-8369918; COSMIC: COSV56848429; COSMIC: COSV56848429;